Deciphering the predictive value of senescence-related signature in lung adenocarcinoma: Implications for antitumor immunity and immunotherapy efficacy

Yufeng Guo ^1,2,3, Yang Wang ⁴, Jianchun Duan ^2,3

⁰Department of Clinical Research, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, China.

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August 30, 2024

View abstract on PubMed

Summary

This study developed a senescence-related gene signature to predict lung adenocarcinoma (LUAD) patient outcomes and immunotherapy response. Lower signature expression indicates better response to immune checkpoint inhibitors.

Area Of Science

Oncology
Cellular Biology
Immunology

Background

Cellular senescence plays a critical role in lung adenocarcinoma (LUAD) development and progression.
Senescent cells have a complex, dual role in LUAD, affecting tumor growth, immune evasion, metastasis, and treatment resistance.
Understanding senescence-related gene expression is crucial for LUAD patient stratification and treatment strategies.

Purpose Of The Study

To evaluate the predictive value of a senescence-related gene signature for survival outcomes in LUAD patients.
To assess the association between the senescence-related signature and immunotherapy efficacy in LUAD.
To investigate the role of senescence in LUAD's anti-tumor immunity.

Main Methods

Integrated data from 1449 LUAD cases from public datasets and a Chinese clinical cohort.
Developed a senescence-related signature using LASSO Cox regression on 156 senescence-associated genes.
Assessed prognostic significance using Kaplan-Meier analysis and time-dependent ROC curves; investigated immune infiltration and gene set variations.

Main Results

Identified a seven-gene senescence signature (FOXM1, VDAC1, PPP3CA, MAPK13, PIK3CD, RRAS, CCND3) with predictive significance in LUAD.
The signature negatively correlated with anti-tumor immunity and neutrophil infiltration.
Low signature expression predicted favorable responses to immune checkpoint inhibitors across multiple solid tumors, including LUAD.
Pharmacological inhibition of FOXM1 showed tumor-suppressive effects and enhanced immunotherapy response in a mouse model.

Conclusions

The developed senescence-related signature holds potential for predicting LUAD patient prognosis.
This signature may also predict immunotherapy efficacy in LUAD patients.
Targeting senescence pathways, like FOXM1 inhibition, could improve LUAD treatment outcomes.

Keywords:

Cellular senescence FOXM1 Immunotherapy LUAD Neutrophils

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